Doutegravir 50mg Tablets

Name: Doutegravir 50mg Tablets

Side effects

The following serious adverse drug reactions are discussed in other sections of the labeling:

  • Hypersensitivity reactions [see WARNINGS AND PRECAUTIONS].
  • Effects on serum liver biochemistries in patients with hepatitis B or C co-infection [see WARNINGS AND PRECAUTIONS].
  • Fat Redistribution [see WARNINGS AND PRECAUTIONS].
  • Immune Reconstitution Syndrome [see WARNINGS AND PRECAUTIONS].

Clinical Trials Experience

Because clinical trials are conducted under widely varying conditions, adverse reaction rates observed in the clinical trials of a drug cannot be directly compared with rates in the clinical trials of another drug and may not reflect the rates observed in practice.

Clinical Trials Experience In Adult Subjects

Treatment-Naïve Subjects: The safety assessment of TIVICAY in HIV-1-infected treatment-naïve subjects is based on the analyses of data from 2 international, multicenter, double-blind trials, SPRING-2 (ING113086) and SINGLE (ING114467) and data from the international, multicenter, open-label FLAMINGO (ING114915) trial.

In SPRING-2, 822 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily, both in combination with fixed-dose dual nucleoside reverse transcriptase inhibitor (NRTI) treatment (either abacavir sulfate and lamivudine [EPZICOM®] or emtricitabine/tenofovir [TRUVADA®]). There were 808 subjects included in the efficacy and safety analyses. Through 96 weeks, the rate of adverse events leading to discontinuation was 2% in both treatment arms.

In SINGLE, 833 subjects were randomized and received at least 1 dose of either TIVICAY 50 mg with fixed-dose abacavir sulfate and lamivudine (EPZICOM) once daily or fixed-dose efavirenz/emtricitabine/tenofovir (ATRIPLA®) once daily (study treatment was blinded through Week 96 and open-label from Week 96 through Week 144). Through 144 weeks, the rates of adverse events leading to discontinuation were 4% in subjects receiving TIVICAY 50 mg once daily + EPZICOM and 14% in subjects receiving ATRIPLA once daily.

Treatment-emergent adverse drug reactions (ADRs) of moderate to severe intensity observed in at least 2% of subjects in either treatment arm in SPRING-2 and SINGLE trials are provided in Table 3. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 3: Treatment-Emergent Adverse Drug Reactions of at Least Moderate Intensity (Grades 2 to 4) and at Least 2% Frequency in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)

System Organ Class/ Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily + 2 NRTIs
(n = 403)		 Raltegravir 400 mg Twice Daily + 2 NRTIs
(n = 405)		 TIVICAY 50 mg + EPZICOM Once Daily
(n = 414)		 ATRIPLA Once Daily
(n = 419)
Psychiatric
  Insomnia < 1% < 1% 3% 3%
  Depression < 1% < 1% 1% 2%
  Abnormal dreams < 1% < 1% < 1% 2%
Nervous System
  Dizziness < 1% < 1% < 1% 5%
  Headache < 1% < 1% 2% 2%
Gastrointestinal
  Nausea 1% 1% < 1% 3%
  Diarrhea < 1% < 1% < 1% 2%
Skin and Subcutaneous Tissue
  Rasha 0 < 1% < 1% 6%
General Disorders
  Fatigue < 1% < 1% 2% 2%
Ear and Labyrinth
  Vertigo 0 < 1% 0 2%
a Includes pooled terms: rash, rash generalized, rash macular, rash maculo-papular, rash pruritic, and drug eruption.

In addition, Grade 1 insomnia was reported by 1% and less than 1% of subjects receiving TIVICAY and raltegravir, respectively, in SPRING-2; whereas in SINGLE the rates were 7% and 4% for TIVICAY and ATRIPLA, respectively. These events were not treatment limiting.

In a multicenter, open-label trial (FLAMINGO), 243 subjects received TIVICAY 50 mg once daily versus 242 subjects who received darunavir 800 mg/ritonavir 100 mg once daily, both in combination with investigator-selected NRTI background regimen (either EPZICOM or TRUVADA). There were 484 subjects included in the efficacy and safety analyses. Through 96 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY and 6% in subjects receiving darunavir/ritonavir. The ADRs observed in FLAMINGO were generally consistent with those seen in SPRING-2 and SINGLE.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: In an international, multicenter, double-blind trial (ING111762, SAILING), 719 HIV-1-infected, antiretroviral treatment-experienced adults were randomized and received either TIVICAY 50 mg once daily or raltegravir 400 mg twice daily with investigator-selected background regimen consisting of up to 2 agents, including at least one fully active agent. At 48 weeks, the rates of adverse events leading to discontinuation were 3% in subjects receiving TIVICAY 50 mg once daily + background regimen and 4% in subjects receiving raltegravir 400 mg twice daily + background regimen.

The only treatment-emergent ADR of moderate to severe intensity with at least 2% frequency in either treatment group was diarrhea, 2% (6 of 354) in subjects receiving TIVICAY 50 mg once daily + background regimen and 1% (5 of 361) in subjects receiving raltegravir 400 mg twice daily + background regimen.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: In a multicenter, open-label, single-arm trial (ING112574, VIKING-3), 183 HIV-1-infected, antiretroviral treatment-experienced adults with virological failure and current or historical evidence of raltegravir and/or elvitegravir resistance received TIVICAY 50 mg twice daily with the current failing background regimen for 7 days and with optimized background therapy from Day 8. The rate of adverse events leading to discontinuation was 4% of subjects at Week 48.

Treatment-emergent ADRs in VIKING-3 were generally similar compared with observations with the 50-mg once-daily dose in adult Phase 3 trials.

Less Common Adverse Reactions Observed in Treatment-Naïve and Treatment-Experienced Trials: The following ADRs occurred in less than 2% of treatment-naïve or treatment-experienced subjects receiving TIVICAY in a combination regimen in any one trial. These events have been included because of their seriousness and assessment of potential causal relationship.

Gastrointestinal Disorders: Abdominal pain, abdominal discomfort, flatulence, upper abdominal pain, vomiting.

Hepatobiliary Disorders: Hepatitis.

Musculoskeletal Disorders: Myositis.

Psychiatric Disorders: Suicidal ideation, attempt, behavior, or completion. These events were observed primarily in subjects with a pre-existing history of depression or other psychiatric illness.

Renal and Urinary Disorders: Renal impairment.

Skin and Subcutaneous Tissue Disorders: Pruritus.

Laboratory Abnormalities

Treatment-Naïve Subjects: Selected laboratory abnormalities (Grades 2 to 4) with a worsening grade from baseline and representing the worst-grade toxicity in at least 2% of subjects are presented in Table 4. The mean change from baseline observed for selected lipid values is presented in Table 5. Side-by-side tabulation is to simplify presentation; direct comparisons across trials should not be made due to differing trial designs.

Table 4: Selected Laboratory Abnormalities (Grades 2 to 4) in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysis) and SINGLE Trials (Week 144 Analysis)

Laboratory Parameter Preferred Term SPRI NG-2 SINGLE
TIVICAY 50 mg Once Daily + 2 NRTIs
(n = 403)		 Raltegravir 400 mg Twice Daily + 2 NRTIs
(n = 405)		 TIVICAY 50 mg + EPZICOM Once Daily
(n = 414)		 ATRIPLA Once Daily
(n = 419)
ALT
  Grade 2 ( > 2.5-5.0 x ULN) 4% 4% 3% 5%
  Grade 3 to 4 ( > 5.0 x ULN) 2% 2% 1% < 1%
AST
  Grade 2 ( > 2.5-5.0 x ULN) 5% 3% 3% 4%
  Grade 3 to 4 ( > 5.0 x ULN) 3% 2% 1% 3%
Total Bilirubin
  Grade 2 (1.6-2.5 x ULN) 3% 2% < 1% < 1%
  Grade 3 to 4 ( > 2.5 x ULN) < 1% < 1% < 1% < 1%
Creatine kinase
  Grade 2 (6.0-9.9 x ULN) 2% 5% 5% 3%
  Grade 3 to 4 ( ≥ 10.0 x ULN) 7% 4% 7% 8%
Hyperglycemia
  Grade 2 (126-250 mg/dL) 6% 6% 9% 6%
  Grade 3 ( > 250 mg/dL) < 1% 2% 2% < 1%
Lipase
  Grade 2 ( > 15-3.0 x ULN) 7% 7% 11% 11%
 Grade 3 to 4 ( > 3.0 x ULN) 2% 5% 5% 4%
Total neutrophils
  Grade 2 (0.75-0.99 x 109) 4% 3% 4% 5%
  Grade 3 to 4 ( < 0.75 x 109) 2% 2% 3% 3%
ULN = Upper limit of normal.

Table 5: Mean Change from Baseline in Fasted Lipid Values in Treatment-Naïve Subjects in SPRING-2 (Week 96 Analysisa) and SINGLE Trials (Week 144 Analysisa)

Laboratory Parameter Preferred Term SPRING-2 SINGLE
TIVICAY 50 mg Once Daily + 2 NRTIs
(n = 403)		 Raltegravir 400 mg Twice Daily + 2 NRTIs
(n = 405)		 TIVICAY 50 mg + EPZICOM Once Daily
(n = 414)		 ATRIPLA Once Daily
(n = 419)
Cholesterol (mg/dL) 8.1 10.1 24.0 26.7
HDL cholesterol (mg/dL) 2.0 2.3 5.4 7.2
LDL cholesterol (mg/dL) 5.1 6.1 16.0 14.6
Triglycerides (mg/dL) 6.7 6.6 13.6 31.9
a Subjects on lipid-lowering agents at baseline were excluded from these analyses (19 subjects in each arm in SPRING-2, and in SINGLE: TIVICAY + EPZICOM n = 30 and ATRIPLA n = 27). Ninety-four subjects initiated a lipid-lowering agent post-baseline; their last fasted on- treatment values (prior to starting the agent) were used regardless if they discontinued the agent  (SPRING-2: TIVICAY n = 9, raltegravir n = 13; SINGLE: TIVICAY + EPZICOM n = 36 and  ATRIPLA: n = 36).

Laboratory abnormalities observed in the FLAMINGO trial were generally consistent with observations in SPRING-2 and SINGLE.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Naïve Subjects: Laboratory abnormalities observed in SAILING were generally similar compared with observations seen in the treatment-naïve (SPRING-2 and SINGLE) trials.

Treatment-Experienced, Integrase Strand Transfer Inhibitor-Experienced Subjects: The most common treatment-emergent laboratory abnormalities (greater than 5% for Grades 2 to 4 combined) observed in VIKING-3 at Week 48 were elevated ALT (9%), AST (8%), cholesterol (10%), creatine kinase (6%), hyperglycemia (14%), and lipase (10%). Two percent (4 of 183) of subjects had a Grade 3 to 4 treatment-emergent hematology laboratory abnormality, with neutropenia (2% [3 of 183]) being the most frequently reported.

Hepatitis B and/or Hepatitis C Virus Co-infection: In Phase 3 trials, subjects with hepatitis B and/or C virus co-infection were permitted to enroll provided that baseline liver chemistry tests did not exceed 5 times the upper limit of normal. Overall, the safety profile in subjects with hepatitis B and/or C virus co-infection was similar to that observed in subjects without hepatitis B or C co-infection, although the rates of AST and ALT abnormalities were higher in the subgroup with hepatitis B and/or C virus co-infection for all treatment groups. Grades 2 to 4 ALT abnormalities in hepatitis B and/or C co-infected compared with HIV mono-infected subjects receiving TIVICAY were observed in 18% vs. 3% with the 50-mg once-daily dose and 13% vs. 8% with the 50-mg twice-daily dose. Liver chemistry elevations consistent with immune reconstitution syndrome were observed in some subjects with hepatitis B and/or C at the start of therapy with TIVICAY, particularly in the setting where anti-hepatitis therapy was withdrawn [see WARNINGS AND PRECAUTIONS].

Changes in Serum Creatinine: Dolutegravir has been shown to increase serum creatinine due to inhibition of tubular secretion of creatinine without affecting renal glomerular function [see CLINICAL PHARMACOLOGY]. Increases in serum creatinine occurred within the first 4 weeks of treatment and remained stable through 96 weeks. In treatment-naïve subjects, a mean change from baseline of 0.15 mg per dL (range: -0.32 mg per dL to 0.65 mg per dL) was observed after 96 weeks of treatment. Creatinine increases were comparable by background NRTIs and were similar in treatment-experienced subjects.

Clinical Trials Experience In Pediatric Subjects

IMPAACT P1093 is an ongoing multicenter, open-label, non-comparative trial of approximately 160 HIV-1-infected pediatric subjects aged 4 weeks to less than 18 years, of which 46 treatment-experienced, INSTI-naïve subjects aged 6 to less than 18 years have been enrolled [see Use in Specific Populations, Clinical Studies].

The adverse reaction profile was similar to that for adults. Grade 2 ADRs reported by more than one subject were decreased neutrophil count (n = 3) and diarrhea (n = 2). There were no Grade 3 or 4 drug-related ADRs reported. No ADRs led to discontinuation.

The Grade 3 or 4 laboratory abnormalities reported in more than one subject were elevated total bilirubin (n = 3) and decreased neutrophil count (n = 2). The changes in mean serum creatinine were similar to those observed in adults.

Postmarketing Experience

In addition to adverse reactions reported from clinical trials, the following adverse reactions have been identified during postmarketing use. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure.

Musculoskeletal

Arthralgia, myalgia.

Patient information

TIVICAY®
(TIV-eh-kay)
(dolutegravir) Tablets

What is the most important information I should know about TIVICAY?

TIVICAY can cause serious side effects, including:

  • Allergic reactions. Call your healthcare provider right away if you develop a rash with TIVICAY. Stop taking TIVICAY and get medical help right away if you:
    • develop a rash with any of the following signs or symptoms:
      • fever
      • generally ill feeling
      • extreme tiredness
      • muscle or joint aches
      • blisters or sores in mouth
      • blisters or peeling of the skin
      • redness or swelling of the eyes
      • swelling of the mouth, face, lips, or tongue
      • problems breathing
    • develop any of the following signs or symptoms of liver problems:
      • your skin or the white part of your eyes turns yellow (jaundice)
      • dark or “tea-colored” urine
      • light-colored stools (bowel movements)
      • nausea
      • loss of appetite for several days or longer
      • pain, aching, or tenderness on the right side of your stomach area

What is TIVICAY?

TIVICAY is a prescription medicine that is used together with other antiretroviral medicines to treat Human Immunodeficiency Virus (HIV-1) infection in adults and children who weigh at least 66 pounds.

HIV-1 is the virus that causes Acquired Immune Deficiency Syndrome (AIDS).

It is not known if TIVICAY is safe and effective in children who weigh less than 66 pounds or in children who have received certain types of medicine for HIV-1 infection.

Who should not take TIVICAY?

Do not take TIVICAY if you:

  • have ever had an allergic reaction to a medicine that contains dolutegravir (TIVICAY, TRIUMEQ®).
  • take dofetilide (TIKOSYN®). Taking TIVICAY and dofetilide (TIKOSYN) can cause side effects that may be serious or life-threatening.

What should I tell my healthcare provider before taking TIVICAY?

Before you take TIVICAY, tell your healthcare provider if you:

  • have ever had an allergic reaction to TIVICAY.
  • have had liver problems, including hepatitis B or C infection.
  • have any other medical condition.
  • are pregnant or plan to become pregnant. It is not known if TIVICAY will harm your unborn baby. Tell your healthcare provider if you become pregnant while taking TIVICAY.
    Pregnancy Registry. There is a pregnancy registry for women who take antiretroviral medicines during pregnancy. The purpose of this registry is to collect information about the health of you and your baby. Talk to your healthcare provider about how you can take part in this registry.
  • are breastfeeding or plan to breastfeed. Do not breastfeed if you take TIVICAY.
    • you should not breastfeed if you have HIV-1 because of the risk of passing HIV-1 to your baby. Talk with your healthcare provider about the best way to feed your baby.

Tell your healthcare provider about the medicines you take, including prescription and over-the-counter medicines, vitamins, or herbal supplements.

Some medicines interact with TIVICAY. Keep a list of your medicines and show it to your healthcare provider and pharmacist when you get a new medicine. You can ask your healthcare provider or pharmacist for a list of medicines that interact with TIVICAY.

Over-the-counter medicines that interact with TIVICAY include:

  • St. John's wort (Hypericum perforatum). Avoid use of St. John's wort with TIVICAY.
  • antacids, laxatives, or other medicines that contain aluminum, magnesium, sucralfate (CARAFATE®), or buffered medicines. TIVICAY should be taken at least 2 hours before or 6 hours after you take antacids, laxatives, or other medicines that contain aluminum, magnesium, sucralfate (CARAFATE), or buffered medicines.
  • iron or calcium supplements taken by mouth. Supplements containing calcium or iron may be taken at the same time with TIVICAY if taken with food. Otherwise, TIVICAY should be taken at least 2 hours before or 6 hours after you take these medicines.
  • Do not start taking a new medicine without telling your healthcare provider. Your healthcare provider can tell you if it is safe to take TIVICAY with other medicines.

How should I take TIVICAY?

  • Take TIVICAY exactly as your healthcare provider tells you to take it.
  • If you miss a dose of TIVICAY, take it as soon as you remember. Do not take 2 doses at the same time or take more than what your healthcare provider tells you to take.
  • Stay under the care of a healthcare provider during treatment with TIVICAY.
  • TIVICAY may be taken with or without food.
  • Do not run out of TIVICAY. The virus in your blood may increase and the virus may become harder to treat. When your supply starts to run low, get more from your healthcare provider or pharmacy.
  • If you take too much TIVICAY, call your healthcare provider or go to the nearest hospital emergency room right away.

What are the possible side effects of TIVICAY?

  • TIVICAY can cause serious side effects including:
  • See “What is the most important information I should know about TIVICAY?”
  • Changes in liver tests. People with a history of hepatitis B or C virus may have an increased risk of developing new or worsening changes in certain liver tests during treatment with TIVICAY. Your healthcare provider may do tests to check your liver function before and during treatment with TIVICAY.
  • Changes in body fat can happen in people who take HIV-1 medicines. These changes may include increased amount of fat in the upper back and neck (“buffalo hump”), breast, and around the middle of your body (trunk). Loss of fat from the legs, arms, and face may also happen. The exact cause and long-term health effects of these problems are not known.
  • Changes in your immune system (Immune Reconstitution Syndrome) can happen when you start taking HIV-1 medicines. Your immune system may get stronger and begin to fight infections that have been hidden in your body for a long time. Tell your healthcare provider right away if you start having new symptoms after you start taking TIVICAY.
  • The most common side effects of TIVICAY include:
    • trouble sleeping
    • tiredness
    • headache

Tell your healthcare provider about any side effect that bothers you or that does not go away.

These are not all the possible side effects of TIVICAY. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088.

How should I store TIVICAY?

  • Store TIVICAY at room temperature between 68°F to 77°F (20°C to 25°C).
  • The bottle of TIVICAY (10-mg tablets) contains a desiccant packet to help keep your medicine dry (protect it from moisture). Keep the desiccant packet in the bottle. Do not remove the desiccant packet. Store TIVICAY 10-mg tablets in the original bottle. Keep the bottle tightly closed and protected from moisture.

Keep TIVICAY and all medicines out of the reach of children.

General information about the safe and effective use of TIVICAY.

Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use TIVICAY for a condition for which it was not prescribed. Do not give TIVICAY to other people, even if they have the same symptoms you have. It may harm them. You can ask your healthcare provider or pharmacist for information about TIVICAY that is written for health professionals. For more information, go to www.TIVICAY.com or call 1-877-844-8872.

What are the ingredients in TIVICAY?

Active ingredient: dolutegravir sodium.

Inactive ingredients: d-mannitol, microcrystalline cellulose, povidone K29/32, sodium starch glycolate, and sodium stearyl fumarate. The tablet film-coating contains the inactive ingredients iron oxide yellow (for the 25-mg and 50-mg tablets), macrogol/PEG, polyvinyl alcohol-part hydrolyzed, talc, and titanium dioxide.

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© Tivicay Patient Information is supplied by Cerner Multum, Inc. and Tivicay Consumer information is supplied by First Databank, Inc., used under license and subject to their respective copyrights.

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